Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron‐dependent lipid peroxide accumulation. Ferroptotic cell death is characterized by cytological changes, including cell volume shrinkage and increased mitochondrial membrane density. Ferroptosis can be induced by two classes of small‐molecule substances known as class 1 (system X c − inhibitors) and class 2 ferroptosis inducers [glutathione peroxidase 4 (GPx4) inhibitors]. In addition to these small‐molecule substances, a number of drugs (e.g. sorafenib, artemisinin and its derivatives) can induce ferroptosis. Various factors, such as the mevalonate (MVA) and sulphur‐transfer pathways, play pivotal roles in the regulation of ferroptosis. Ferroptosis plays an unneglectable role in regulating the growth and proliferation of some types of tumour cells, such as lymphocytoma, ductal cell cancer of the pancreas, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Here, we will first introduce the discovery of and research pertaining to ferroptosis; then summarize the induction mechanisms and regulatory pathways of ferroptosis; and finally, further elucidate the roles of ferroptosis in human tumourous diseases.

Ribosomal protein s15a (RPS15A) plays a promotive role in the mRNA/ribosome interactions during early translation. Our previous study has found that inhibiting RPS15A expression can decrease proliferation and induce cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism underlying the involvement of RPS15A in HCC pathogenesis and the clinical significance of RPS15A expression remain unclear. In this study, an evaluation of RPS15A expression in 110 surgically resected HCCs and matched tumor-adjacent normal tissues revealed an overexpression of RPS15A in HCC, which was correlated with worse survival. In addition, tumor tissue with higher RPS15A expression demonstrated a higher microvascular density (MVD). Subsequently, two HCC cell lines, Huh7 (low-level constitutive RPS15A expression) and HepG2 (high RPS15A expression) were used to further evaluate the role of RPS15A in angiogenesis. The co-culture experiment of HCC cells with endothelial cells revealed that the induced overexpression of RPS15A in Huh7 cells increased the angiogenic potential of HUVEC in a paracrine fashion; conversely, knockdown of RPS15A in HepG2 cells showed an opposite effect. Further analysis indicated that RPS15A modulated FGF signaling by enhancing Wnt/beta-catenin-mediated FGF18 expression in HCC cells. FGF18, in turn, through binding to its FGFR3 receptor on endothelial cells, can activate the AKT and ERK pathway and promotes angiogenesis in a tumor microenvironment. Our in vivo experiment further confirmed that inhibition of RPS15A expression in HCC xenografts dramatically hindered tumor growth and inhibited tumor angiogenesis. Together, our findings suggest that RPS15A promotes angiogenesis in HCCs by enhancing Wnt/beta-catenin induced FGF18 expression. The RPS15A/FGF18 pathway may be a rational target for anti-angiogenic therapy of HCC.

Ribosomes, which are important sites for the synthesis of proteins related to expression and transmission of genetic information in humans, have a complex structure and diverse functions. They consist of a variety of ribosomal proteins (RPs), ribosomal RNAs (rRNAs) and small nucleolar RNAs. Owing to the involvement of ribosomes in many important biological processes of cells, their major components, rRNAs and RPs, have an important role in human diseases, including the initiation and evolvement of malignancies. However, the main mechanisms underlying the involvement of ribosomes in cancer remain unclear. This review describes the crucial role of ribosomes in various common malignant tumors; in particular, it examines the effects of RPs, including S6, the receptor for activated C-kinase and RPS15A, on the development and progression of hepatocellular carcinoma.

Cholangiocarcinoma (CCA) is a relatively rare malignant and lethal tumour derived from bile duct epithelium and the morbidity is now increasing worldwide. This disease is difficult to diagnose at its inchoate stage and has poor prognosis. Therefore, a clear understanding of pathogenesis and major influencing factors is the key to develop effective therapeutic methods for CCA. In previous studies, canonical correlation analysis has demonstrated that tumour microenvironment plays an intricate role in the progression of various types of cancers including CCA. CCA tumour microenvironment is a dynamic environment consisting of authoritative tumour stromal cells and extracellular matrix where tumour stromal cells and cancer cells can thrive. CCA stromal cells include immune and non‐immune cells, such as inflammatory cells, endothelial cells, fibroblasts, and macrophages. Likewise, CCA tumour microenvironment contains abundant proliferative factors and can significantly impact the behaviour of cancer cells. Through abominably intricate interactions with CCA cells, CCA tumour microenvironment plays an important role in promoting tumour proliferation, accelerating neovascularization, facilitating tumour invasion, and preventing tumour cells from organismal immune reactions and apoptosis. This review summarizes the recent research progress regarding the connection between tumour behaviours and tumour stromal cells in CCA, as well as the mechanism underlying the effect of tumour stromal cells on the growth of CCA. A thorough understanding of the relationship between CCA and tumour stromal cells can shed some light on the development of new therapeutic methods for treating CCA.

Cholangiocarcinoma (CCA) is a malignant hepatic tumor with a poor prognosis, which needs early diagnosis urgently. The gut microbiota has been shown to play a crucial role in the progression of liver cancer. Here, we explored a gut microbiota model covering genera Burkholderia-Caballeronia-Paraburkholderia, Faecalibacterium, and Ruminococcus_1 (B-F-R) for CCA early diagnosis. A case-control study was conducted to enroll 53 CCA patients, 47 cholelithiasis patients, and 40 healthy controls. The feces samples and clinical information of participants were collected in the same period. The gut microbiota and its diversity of individuals were accessed with 16S rDNA sequencing, and the gut microbiota profile was evaluated according to microbiota diversity. Finally, four enriched genera in the CCA group (genera Bacteroides, Muribaculaceae_unclassified, Muribaculum, and Alistipes) and eight enriched genera in the cholelithiasis group (genera Bifidobacterium, Streptococcus, Agathobacter, Ruminococcus_gnavus_group, Faecalibacterium, Subdoligranulum, Collinsella, Escherichia-Shigella) constitute an overall different microbial community composition (P = 0.001). The B-F-R genera model with better diagnostic value than carbohydrate antigen 19-9 (CA19-9) was identified by random forest and Statistical Analysis of Metagenomic Profiles (STAMP) to distinguish CCA patients from healthy controls [area under the curve (AUC) = 0.973, 95% CI = 0.932–1.0]. Moreover, the correlative analysis found that genera Burkholderia-Caballeronia-Paraburkholderia were positively correlated with body mass index (BMI). The significantly different microbiomes between cholelithiasis and CCA were found via principal coordinates analysis (PCoA) and linear discriminant analysis effect size (LEfSe), and Venn diagram and LEfSe were utilized to identify four genera by comparing microbial compositions among patients with malignant obstructive jaundice (MOJ-Y) or not (MOJ-N). In brief, our findings suggest that gut microbiota vary from benign and malignant hepatobiliary diseases to healthy people and provide evidence supporting gut microbiota to be a non-invasive biomarker for the early diagnosis of CCA.

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Cholangiocarcinoma (CCA) is a fatal disease with dismal survival rates. Long non-coding RNA (lncRNA) expression profiling as potential prognostic biomarkers play critical roles in tumor initiation, development, and poor prognosis. Identifying specific lncRNA to predict the prognosis of CCA patients in the early stages is very important for improving a patient’s survival. In the current study, we aimed to establish a novel risk-stratification lncRNA signature panel in CCA. The initial lncRNA discovery was identified in The Cancer Genome Atlas database (TCGA cohort). The Cox regression analysis was used to establish the lncRNA prognostic model and the receiver operating characteristic (ROC) curve analysis was performed to assess the specificity and sensitivity of the model. This was followed by independent validation of the lncRNA signature in the CCA patients from the First Affiliated Hospital of Wenzhou Medical University (WMU cohort). Furthermore, by using the Gene Ontology function and Kyoto Encyclopedia Gene and Genome pathway enrichment analysis, we explored the potential function of prognosis lncRNA. Finally, five lncRNA (HULC; AL359715.5; AC006504.8; AC090114.2; AP00943.4) were screened to establish the predictive model that significantly associated with poor overall survival(HR:4.879;95%CI,1.587-14.996; p =0.006). This five-lncRNA signature model showed excellent accuracy in the TCGA cohort (AUC=0.938), and also robustly predicted survival in the validation WMU cohort(AUC=0.816). Functional enrichment analysis suggested prognostic lncRNA was primarily associated with CCA-related biological processes. Our data established a novel lncRNA signature model for CCA risk-stratification and robust identification of CCA patients with poor molecular genotypes. Moreover, it revealed new molecular mechanisms of CCA.

Understanding the occurrence, development, and treatment of liver diseases is the main goal of hepatopathology research. Liver diseases are not only diverse but also highly heterogeneous among individuals. At present, research on liver diseases is conducted mainly through cell culture, animal models, pathological specimens, etc . However, these methods cannot fully reveal the pathogenic mechanism and therapeutic characteristics of individualized liver diseases. Recent advances in three-dimensional cell culture technology (organoid culture techniques) include pluripotent stem cells and adult stem cells that are cultured in vitro to form self-organizing properties, making it possible to achieve individualized liver disease research. This review provides a comprehensive overview of the development of liver organoids, the existing and potential applications of liver regenerative medicine, the pathogenesis of liver disease heterogeneity, and drug screening.